Preclinical study of OQL051, a gut-restricted CDK4/6 inhibitor for chemotherapy-induced diarrhea.
Authors: Robert Claude Tyler, Wenqin Zeng, Wenxi Li, Liping Chen, Shilan Liu, Shiyi Zhang
Journal: Journal of Clinical Oncology (2022)

e24085 Background: Chemotherapy-induced diarrhea (CID) is a potentially life-threatening AE (incidence 50-80% with 5FU/irinotecan). Chemotherapy dose reduction or discontinuation is often required. Cyclin-dependent kinases 4/6 (CDK4/6) regulate cell cycle G1/S transition and can induce a “pharmacological quiescence”. Transient administration of a gut-restricted CDK4/6 inhibitor, prior to chemotherapy may slow/inhibit intestinal stem/epithelial cell cycling and thus, be prophylactic for CID. Methods: OQL051 (OQL), a gut restricted CDK4/6 inhibitor, was studied in MCF7 cells treated with OQL (2x serial dilution, max 10 µM) to measure cell proliferation inhibition. Colo205 cells were treated with OQL 2x serial dilution (25 µM max) to determine the protective effect of OQL on 5-FU. Measurements were performed using Cell Titer -Glo Luminescent cell Viability and caspase 3/7 assay kits. OQL PK was studied in Balb/c mice given OQL, 50 mg/kg intra-gastrically. Blood samples were collected at pre- and 0.25, 0.5, 1, 2, 4, and 6 h post-dosing. Tissues (jejunum/colon) were collected at 0.5, 2, and 6 h after OQL (n = 3/collection). Plasma and tissues were analyzed for OQL by LC-MS. CID (5FU model) was studied in 5 groups of Balb/c mice (n = 5/grp) given OQL vehicle (OQLV) +0.9%NaCl saline (NaCl), OQLV +5FU (175 mg/kg) and OQL+5FU at 3 OQL doses (25, 50, and 100 mg/kg) orally prior to 5FU injection. CID (irinotecan) model) was studied in Balb/c mice given OQL+ Irinotecan at 2 OQL doses (25 and 50 mg/kg, n = 5/ dose) plus IP Irinotecan. OQLV or OQL were given orally prior to IP Irinotecan. Diarrhea and intestine tissue damage were analyzed to evaluate the efficacy. Results: OQL treated MCF7 cells showed conc.-dependent growth inhibition (IC 50 0.81 uM). Colo205 cells treated with 5-FU (10 µM) suppressed cell proliferation (60% @ 48 h). Pre-treatment with OQL decreased 5-FU inhibition/apoptosis in a dose-dependent manner. Jejunum and colon OQL conc. were 300x &gt; plasma (AUC 12017, 10515 vs 32 ng·h/g). OQL decreased CID (5FU) grades and protected the intestinal epithelium. On day 6 post-treatment, the OQL group had mice normal (80%) and mild intestinal damage (20%) vs. OQLV group had mice normal (20%), mild intestinal damage (20%), and severe intestinal damage (60%). In the Irinotecan model, OQL showed efficacy similar to the 5FU model. On day 7 post-treatment, OQL had 40% of mice normal and 60% with mild tissue damage (grade 1) vs. OQLV with 0% normal, 40% mild, and 60% with severe intestinal damage. Histology showed intestinal tissues /epithelial cells had less edema, inflammation, and necrosis after OQL vs. OQLV. Conclusions: An oral CDK4/6 inhibitor, OQL051, was restricted to the intestinal lining and reduced 5FU intestinal cell apoptosis, necrosis, and inflammation. In a preclinical model, prophylactically used OQL051 improved not only diarrhea but also intestine damage status which supports the potential for a prophylactic CID treatment.